It is common knowledge that pathogens of bacterial infectious diseases become resistant under the influence of antibiotic therapy under selection pressure, among other reasons also more quickly for a false and too frequent administration of antibiotics. Special problems have been increasingly caused by infections that are provoked by multiresistant gram-positive bacteria, such as staphylococcus aureus, or by glycopeptide-resistant enterococci; in case of hospitalism, in patients whose immune system is undermined they can lead to serious diseases. The multiresitances developed in these germs make the treatment more difficult because therapeutic agents do not exist any longer. Vancomycin (a glycopeptide) is the reserve antibiotic to treat serious infections with multiresistant staphylococci (MRSA). Up to now, the vanA-type vancomycin resistance has only been observed in enterococci (VRE) without the extreme multiresistant problem like in MRSA. The interspecific transfer of the vanA-type resistance of enterococci to staphylococci, which has been feared for a long time, occurred in the USA in 2002 for the first time. In these staphylococcus aureus strains that are highly resistant against vancomycin the vanA gene is integrated into a multiresistant plasmid (Gottlieb, S. BMJ 326; 783(2003)).
These developments and the partly underestimated necessity for intensive searches for new structures and targets have led to a lack of sufficiently effective therapeutic agents. To ensure the curing of bacterial diseases and to be able to treat infections with resistances against antibiotics, new substances with antibiotic effects are urgently required (see for example Gräfe, Biochemie der Antibiotika (Biochemistry of antibiotics), Spektrum Heidelberg 1992; S. Grabley, R. Thiericke & U. Gräfe, Drug Discovery from Nature, Springer, S. 281-301, 1999). For the just explained reason, new antibiotics that can overcome the described resistance barriers become more and more important. In addition to this, other disadvantages such as the insufficient scope of efficiency, unfavorable pharmacokinetics and the side effects of the currently available antibiotics should be overcome.
Therefore, it is the object of the present invention to make a new microbial agent with an original structure and good anti-microbial characteristics, against multiresistant germs in particular, available.
According to the invention, this task is fulfilled by the fact that the actinomycete strain streptomyces sp. HKI 0179 is fermented in a liquid growth medium with carbon and nitrogen sources as well as usual inorganic salts till the new anti-microbial agent, hereinafter referred to as HKI10311129,accumulates in the culture solution and can be isolated from it in a pure form afterwards. The streptomyce strain KI 0179 was deposited as DSM 13059 at the Deutschen Sammlung für Mikroorganismen und Zellkulturen (DSMZ) (German Collection for Microorganisms and Cell Cultures) in Braunschweig, Mascheroder Wege 1.
The difference between HKI10311129 and the antibiotics known till now is the innovative character of the chemical structure of HKI10311129 that has been demonstrated by physicochemical measurements without doubt. (Tables 1 and 2).
Antimicrobial effects are not known for related structures that are described in the Japanese patent 94 339 395, in CA 122, 237919g and in J. Antibiot., 45 (1992), 1974-6. For a further related structure, described in J. Antibiot. 51 (1998), 21-25, 26-32, an activity against methicillin resistant staphylococci is certainly known, but an activity against enterococci and particularly against strains with a vanA-type vancomycin-resistance is not known.
Although the antibiotic altamiramycin has already been known from the streptomyce strain DSM 13059 (DE 100 65 606), the new antimicrobial agent HKI10311129 has been discovered now. It has a surprisingly strong antibacterial effect against gram-positive bacteria, against multiresistant germs such as staphylococci and enterococci in particular. HKI10311129 can be particularly used for men and animals as a medicine against infections with multiresistant gram-positive germs, the ones with a vanA-type glycopeptide resistance included.